Monoclonal antibodies directed against tumor-associated antigens expressed on the tumor cell surface and therefore capable of targeting such tumors have found application in the immunodiagnosis and immunotherapy of human tumors. For example, a monoclonal antibody directed against such an antigen may be tagged with a radioactive, or other, detectable label and used for cancer diagnosis. Additionally, therapeutic uses of monoclonal antibodies are being developed by labelling the antibody with a quantity of a radioactive isotope or a toxic ligand to damage or destroy the targeted tumor.
The interaction of certain monoclonal antibodies directed against tumor cells with cell surface antigens is well documented. See, for example, H. Koprowski, et alli, Proc. Natl. Acad. Sci. USA, 81:216-222 (1983) [Koprowski I]; M. Herlyn et al, Adv. Cancer Res., 49:189-221 (1987) [Herlyn I]; H. Koprowski, et alli, Somat. Cell. Mol. Genet., 11:297-302 (1985) [Koprowski II]; and H. F. Sears, et alli, Contr. Oncol., 19:180-192 (1984) [Sears I] among others.
A special class of anti-tumor monoclonal antibodies is represented by those antibodies that recognize surface receptors for growth factors. See, e.g., H. Ross, et alli, Proc. Natl. Acad. Sci. USA, 81:6681-6685 (1984) [Ross I]; P. M. Grob, et alli, J. Biol. Chem., 260:8044-8049 (1985); and U. Murthy, et alli, Arch. Biochem. Biophys., 252:549-560 (1987) among others.
In present immunotherapy, the selection of a monoclonal antibody for use in treating a certain tumor type is based on the binding of the monoclonal antibody to the cell surface antigen against which the antibody is directed. Monoclonal antibodies, particularly, mouse monoclonal antibodies of the IgG2A isotype, have been observed to destroy human cancer cells implanted in athymic nude mice. The tumoricidal effect seems to be mediated by the monoclonal antibody through interaction with Fc receptors of mouse or human macrophages. Monoclonal antibodies of an isotype other than IgG2A which do not interact with Fc receptors have not been observed to mediate destruction of cancer cells. The presently employed methods of selecting a monoclonal antibody for immunotherapy deal with interaction between the monoclonal antibody and surface of the cell only.
These present methods for selecting an antibody for therapeutic treatment are inadequate in view of recent scientific observations that some antibodies simply attach to the antigen, while other monoclonal antibodies are taken up intracellularly and translocated to the cell nucleus. For example, one monoclonal antibody 425 (IgG2A) directed against the EGF receptor was observed to be translocated to the nucleus in intact cells instead of the original ligand. Another monoclonal antibody directed against the Y determinant expressed on EGF receptor of tumor cell lines was translocated into the nucleus of colorectal carcinoma but not epidermoid carcinoma cells [E. M. Rakowicz-Szulczynska, et alli, Arch. Biochem. Biophys., 268:456-464 (1989)].
These observations suggest that certain monoclonal antibodies may be more desirable than others for therapeutic activity in tumor cells and that the present methods for selection of antibodies for therapeutic use are inadequate.
Additional disadvantages in the present use of monoclonal antibodies in immunotherapy include the current lack of knowledge of dosage levels of antibody and radioactive or toxic ligands attached thereto. In current practice the dosage of a labelled antibody to which is attached a radioactive label or toxin to be administered to the patient is simply grossly estimated based on the size of the patient's tumor.
Preferably, antibody therapy should employ a sufficient dosage to kill the tumor cell to which the antibody attaches and yet decrease as much as possible the side effects of the radioactivity or toxin on the healthy tissue of the patient. Inaccurate dosage can often result in the patient being exposed to either excessive amounts of radioactivity or toxin with their attendant serious side effects, or inadequate amounts of radioactivity or toxin to destroy the tumor.
There exists therefore a need in the field of immunotherapy for methods for the selection of appropriate monoclonal antibodies in suitable dosages for the treatment of certain tumors.